Although the present invention disclosed in this application has applicability to a number of different cancers and disorders, only the background of selected representative cancers and autoimmune diseases is described for illustrative purposes.
A. Renal Cell Cancer
The annual incidence of renal cell cancer in the U.S. is approximately 30,000 cases, and this disease accounts for about 2.5% of cancer deaths in men and 1.8% in women. Diagnosis of the disease is so difficult that it has been called "the internist's tumor." This is due to the subtle clinical symptoms of this nearly silent killer.
About 10% of patients presenting with renal cancer have the symptoms of pain, hematuria and a flank mass of tissue, which are evidence of far advanced disease. In most cases, the cancer is found during a diagnostic study to discover a cause for a vague set of symptoms in an unwell patient. Current diagnostic methods include intravenous pyelography, ultrasound, MRI, CT, radionuclide scanning and aspiration and biopsy of a cyst. All methods are limited in their ability to distinguish cancerous from normal tissue, but tend to be very good at identifying cysts. Due to the association of other urinary tract cancers with renal cancer, it is recommended practice to routinely perform a cystoscopy to search for cancers of the urinary tract when a diagnosis of renal cancer has been made (Cancer Manual, 9th ed., 1996, American Cancer Society, Massachusetts Division, Framingham, Mass., pp. 434-445).
B. Cervical Cancer
The annual incidence of cervical cancer in the U.S. is estimated at 15,700 cases for 1996. Although this disease is highly treatable, approximately 4,900 patients die annually.
Risk of cervical cancer among women is difficult to determine. Therefore, the American College of Obstetrics and Gynecology recommends that most women undergo an annual cytological diagnostic test for cervical cancer, the Pap test. The diagnostic performance of the Pap test is good (false negative rate 5%-30%, false positive rate &lt;5%), but the test suffers from a significant percentage of equivocal results, which are referred to as atypia. It is then recommended that smears which are atypical or show evidence of inflammation be repeated after any current infection has been successfully treated. The frequency of atypical results not only increases test costs, but also increases the risk to the average patient, since the major difficulty with the use of the Pap test as a screening tool is patient compliance. Further diagnostic procedures, and there are many, are all invasive to varying degrees.
C. Bladder Cancer
Bladder cancer is the fifth most common cancer in the United States. The American Cancer Society estimated that in 1996 a total of 52,900 new cases would be detected and that there would be 11,700 deaths resulting from this disease. The incidence of bladder cancer increases with age. It is more common in men than in women by a ratio of approximately three to one and has been shown to be highly associated with smoking as well as exposure to certain dyes. The most common type of bladder cancer is transitional cell carcinoma (TCC), representing greater than 90% of all cases.
The most common presenting symptoms are hematuria, which is observed in approximately 80% of the cases, and dysuria. Although hematuria is more often related to nonmalignant conditions, it is recommended that in the presence of such symptoms an evaluation for bladder cancer be completed. Once infection of the urinary tract has been eliminated as a possibility, a full evaluation is likely to include urine cytology, intravenous pyelography and cystoscopy. The possibility of a positive diagnosis by cytology (i.e., the identification of tumor cells in voided urine) increases with the grade of the tumor. In some cases cytological evaluation may be necessary to detect tumor in situ or tumors which are located in the upper end of the bladder. Careful cystoscopic examination, with multiple biopsies taken in areas in and around a suspected tumor, is considered to be the gold standard for diagnosis of bladder cancer. Intravenous pyelography may aid in accurately determining the stage of the tumor.
Following the initial procedures for evaluation, transurethral biopsy and resection are usually performed. These enable removal of the apparent lesion and provide information regarding the clinical stage and extent of invasion of the tumor. Such information aids in the selection of appropriate therapeutic approaches and of subsequent monitoring procedures. As recurrence of superficial tumors is common, occurring in 75% of the cases, usually within 12 months after treatment, monitoring is crucial for the long-term survival of the patient. Therefore, patients with superficial TCC are typically monitored every three months for the first two years and, if there has been no recurrence, every six months during the following year. Because cystoscopy is invasive and unpleasant and because the reliability of urine cytology is variable in detecting recurrence, there is a significant need for a reliable, non-invasive diagnostic method.
D. Colorectal Cancer
The annual rate of incidence of colorectal cancer has fallen significantly since 1970. However, the estimate of new cases in the U.S. for 1996 was still 133,500, with a corresponding projection of 54,900 deaths. Colorectal cancer is third in incidence for both men and women in the U.S.
The key to falling incidence has been the advent of early detection, which has been made possible by the use in the U.S. of screening protocols. Screening includes testing for the presence of occult blood in stool specimens (by use of a product such as Hemoccult.RTM.), digital rectal examination, and sigmoidoscopy. The latter two procedures must be performed in the clinician's office and are not capable of detecting disease in the lateral or ascending colon. Therefore, not only is the presence of cancer often missed, but the clinician is left to guess whether to utilize additional procedures in order to visualize the entire colon. Such procedures, which include direct visualization by colonoscopy or X-ray visualization after giving a barium enema, are invasive, expensive, and time consuming.
The procedure for screening recommended by the American Cancer Society is colonoscopy, in that it allows the removal of polyps and biopsy of suspicious lesions at the time of the procedure. The decision to proceed with colonoscopy is based on the positive result of an occult blood test, a procedure with a sensitivity of approximately 37% and a specificity of approximately 97%.
The American Cancer Society recommends, for general screening, an annual digital rectal exam for all individuals beginning at age 40. At age 50, the Society further recommends initiation of an annual series of three double tests for occult blood by the guaiac method. Finally, the Society recommends that two initial sigmoidoscopies be performed one year apart, and that, if both are negative, further visualization by sigmoidoscopy be repeated every three to five years.
Patients diagnosed with colon cancer are often monitored with one or more blood tests for circulating tumor associated antigens, such as CEA or CA72-4 4. However, these markers are not capable of detecting early stage disease (A or B1 by the Dukes staging system), which can be readily treated, and are, therefore, not suitable for screening of the general population.
Accordingly, there is a need in the art for a non-invasive diagnostic method with reliability in detecting occurrence or recurrence of certain cancers. The present invention fulfills this need and further provides other related advantages.
E. Autoimmune Diseases
Autoimmune diseases are complex and have diverse mechanisms and pathologies. For clarity, diseases that are known to be mediated by production of specific antibodies to self-antigens, with the result being the destruction of host tissue, are described.
Antibodies to basement membranes of lung and kidney glomeruli are produced by individuals with Goodpasture's syndrome, to skin basement membrane in individuals with pemphigoid syndrome, and to collagen in rheumatoid arthritis. The pathologic progression of the disease involves the deposition of specific antibodies to normal constituents in the skin, kidneys, lungs or joints, followed by destruction of the basement membranes by complement activation and by cellular inflammatory processes. These processes result in tissue destruction that accelerates with age, and which current treatments can ameliorate but not control or cure.
Many of the molecules that stimulate the accumulation of immune cells at a site of inflammation are products of the activated complement system. For example, component C3 is proteolytically activated to C3b, which attaches to the membrane target to be destroyed. The portion of C3 that is removed, a 9 kd peptide from the alpha chain of C3 designated C3a, is a key attractor of monocytes and macrophages to sites of tissue destruction.
Accordingly, therefore, there is a need in the art for agents which can inhibit the formation of such active components to control the processes which ultimately lead to the destruction of tissues in autoimmune diseases. The present invention fulfills this need and further provides other related advantages.